Proteolipid protein (PLP) is the major protein component of central nervous system (CNS) myelin and is now recognized as a major autoantigen involved in the development of experimental autoimmune encephalomyelitis (EAE), an experimental model for human multiple sclerosis (MS). Just as MS is known to occur in certain human populations at a higher frequency, it is also known that some strains of mice are susceptible (e.g. SJL) while others are resistant (e.g. B10.S), even though the mice are H-2 identical. PLP 139-151 (HSLGKWLGHPDKF) is the dominant antigen for the induction of EAE in SJL mice, and we have found that the number of PLP 139-151 reactive T cells in the naive SJL repertoire is very high (1:20,000). In spite of this the SJL mice do not develop spontaneous EAE. We believe this is because SJL mice possess two different repertoires, that both recognize PLP 139-151, but which differ in their fine specificity and function in that one is pathogenic and the other is protective. We have developed two T cell receptor (TcR) transgenic mice which are representative of each of these repertoires. The transgenic mice expressing a pathogenic TcR develop EAE, whereas the mice expressing a non-pathogenic TcR do not. We have also generated an IAS/PLP 139-151 tetramer which binds and stains pathogenic T cells in transgenic and non-transgenic SJL mice. In this grant we propose to study the role of the two repertoires in the induction and regulation of EAE. We propose to: 1) Study the selection, expansion, differentiation and interplay between the two PLP 139-151 specific T cell repertoires in susceptible and resistant mice. By using the tetramers we will determine a) how the PLP 139-151 specific T cells expand and differentiate and b) how the two PLP 139-151 specific repertoires function in the susceptible-SJL and resistant-B 10.S mice. 2) Determine the cellular basis for the difference in susceptibility to EAE in SJL and B1O.S mice. By using transgenic T cells from the SJL and B10.S mice that express pathogenic TcR we will a) study the role of T cells; b) the role of APCs and their critical molecules (like class II, B7 and IL- 12) in susceptibility/resistance to EAE. 3) Analyze the mechanism by which expression of the alternate T cell repertoire specific for PLP 139-151 induces protection against EAE. Using the TcR transgenic mice that express the alternate TcR repertoire to PLP 139-151, we will a) determine whether these transgenic mice will develop EAE either spontaneously, of following immunization with the PLP 139-151 or other cross-reactive ligands; b) cross the two transgenic mice expressing pathogenic and protective TcRs and analyze the dual TcR transgenic mice for the development of EAE The results will provide basic information on the mechanism by which PLP specific T cells induce autoimmunity of the CNS and how different repertoires balance each other and regulate development of autoimmunity.